Direct evidence indicates that both Abs and CD8+ T cells contribute to restriction of simian immunodeficiency virus (SIV) replication. In the case of CD4+ T cells, however, it has been difficult to ascertain their contribution as they are also the target for viral infection. SIVmac251 infection of macaques is an excellent model whereby to assess these questions. Our lab and others demonstrated that preventive vaccination delays SIV disease in macaques. Cross-sectional studies performed in our infected macaques defined cell-mediated immune response in effector or privileged sites, and prospective studies with optimized T cell vaccines addressed immune correlates of protection from disease. We showed that a combination of DNA and a highly recombinant poxvirus-based SIV vaccine (NYVAC) is superior to NYVAC-SIV alone and that CD8+ central memory T cells (TCM) but not cytotoxic T lymphocytes (CTLs) inversely correlate with protection from disease. Importantly, we provided the first evidence that virus-specific CD4+ T cells also inversely correlate with low levels of primary and chronic viremia. Our next studies demonstrated that the breadth of immune response is important and that antigens encoded by nonstructural viral proteins contribute to protection. As preventive vaccination with T cell vaccines ameliorated the virological outcome following viral challenge, we explored strategies to augment virus-specific immune responses in already infected macaques treated with antiretroviral therapy (ART). We demonstrated in two independent studies that vaccination of SIV-infected ART-treated macaques with either ALVAC-SIV-based or NYVAC-SIV-based vaccines resulted in better control of viral replication after ART interruption. These studies provide the proof of concept to explore therapeutic vaccination approaches in HIV-1-infected individuals. Over the years, our preclinical data provided proof of principle for the initiation and continuation of human trials. ALVAC-HIV-based vaccine candidates are now in a phase III trial in adults in Thailand and a phase I trial in neonates in Uganda is being prepared. The combination of DNA plus NYVAC-HIV will be tested by EuroVac in healthy volunteers. Lastly, therapeutic phase I and II trials with ALVAC-HIV are ongoing at several sites and I plan to perform a phase I therapeutic trial with NYVAC-HIV in the U.S. The induction of poxvirus-specific immunity limits repeated exposure to these viral vectors. How the quality and extent of the vector-induced cellular immune response integrate with the immune response to the transgene has not been fully elucidated. Therefore, we initiated studies in macaques to define the immune responses that limit vaccinia and related poxvirus replication. A surprising byproduct of these studies, highly relevant to the national bioterrorism prevention effort, was the finding that SIV-infected immune-compromised macaques could be vaccinated safely with the smallpox vaccine Dryvax when a highly attenuated poxvirus was used as a prime but nonetheless were not protected against a monkeypox challenge exposure. We demonstrated that Abs alone but not cell-mediated responses conferred protection, and IgM to IgG switching was impaired in conditions of severe CD4+ T cell depletion. These data shed light on the mechanisms of protection of a vaccine that has eradicated a human viral pathogen, and they suggest that, even if HIV-1 immunogens able to induce neutralizing Abs to HIV primary isolates were available, their therapeutic effect in immune-compromised individuals would be limited.